Genome-Wide Functional Synergy between Amplified and Mutated Genes in Human Breast Cancer
Genome-Wide Functional Synergy between Amplified and Mutated Genes in Human Breast Cancer
复制标题
DOI：
10.1158/0008-5472.can-08-3082
复制
发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Polyak, Kornelia
中科院分区：
文献类型：
--
作者：
Nikolsky, Yuri;Sviridov, Evgeny;Polyak, Kornelia
单个癌细胞包含大量的基因改变，这些基因改变结合在一起就会产生恶性表型。然而，扩增和突变的基因是否形成了功能和物理相互作用网络，可以解释具有联合变化的细胞的选择，目前尚不清楚。为了研究这个问题，我们使用密集的单核苷酸多态性阵列研究了191个乳腺肿瘤的拷贝数变化，并识别了1,747个拷贝数增加的基因，这些基因被组织成30个扩增片段。扩增产物在整个基因组中分布不均。每个扩增子在途径、网络和分子功能上都有不同的浓缩模式，但单个扩增子内的基因并不形成连贯的功能单位。扩增片段中的基因包括所有主要的致癌途径，并且高度富含导致乳腺癌的基因。相比之下，乳腺癌中有体细胞突变的1188个基因随机分布在基因组上，不代表一个功能上有凝聚力的基因集，并且乳腺癌标记基因的丰度相对较低。突变和获得的基因没有统计学意义的重叠，但在包括转化生长因子β、WNT、成纤维细胞生长因子和PIP3信号在内的关键致癌途径中具有高度的协同作用。总体而言，在转录调控信号中，突变基因更多地位于获得基因的上游，这表明突变基因主要是调控基因，而获得基因主要是受调控的基因。ESR1是主要的转录因子，调节扩增的基因，但不调节突变的基因。我们的结果支持这样的假设，即多个遗传事件，包括拷贝数增加和体细胞突变，是建立恶性细胞表型所必需的。[癌症资源2008；68(22)：9532-40]
A single cancer cell contains large numbers of genetic alterations that in combination create the malignant phenotype. However, whether amplified and mutated genes form functional and physical interaction networks that could explain the selection for cells with combined alterations is unknown. To investigate this issue, we characterized copy number alterations in 191 breast tumors using dense single nucleotide polymorphism arrays and identified 1,747 genes with copy number gain organized into 30 amplicons. Amplicons were distributed unequally throughout the genome. Each amplicon had distinct enrichment pattern in pathways, networks, and molecular functions, but genes within individual amplicons did not form coherent functional units. Genes in amplicons included all major tumorigenic pathways and were highly enriched in breast cancer-causative genes. In contrast, 1,188 genes with somatic mutations in breast cancer were distributed randomly over the genome, did not represent a functionally cohesive gene set, and were relatively less enriched in breast cancer marker genes. Mutated and gained genes did not show statisticalty signifiicant overlap but were highly synergistic in populating key tumorigenic pathways including transforming growth factor beta, WNT, fibroblast growth factor, and PIP3 signaling. In general, mutated genes were more frequently upstream of gained genes in transcription regulation signaling than vice versa, suggesting that mutated genes are mainly regulators, whereas gained genes are mostly regulated. ESR1 was the major transcription factor regulating amplified but not mutated genes. Our results support the hypothesis that multiple genetic events, including copy number gains and somatic mutations, are necessary for establishing the malignant cell phenotype. [Cancer Res 2008;68(22):9532-40]